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Umur berkaitan dengan terkenanya kanker
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Insiden kanker paru meningkat dengan meningkatnya penggunaan rokok Insiden kanker paru vs kematian a4 – a7
Memiliki tipe kecenderungan yang sama
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Tumorigenesis multistep process Urutan proses perkembangan kanker sampai
terbentuk berbeda Beberapa langkah terjadi dengan frekuensi tinggi
Umur bertambah insiden kanker meningkat
Resiko terjadinya tumor pada mesothelioma pada pekerja yang terdedah asbes (kiri)
percobaan pada mencit – pembentukan tumor kulit akibat asbes
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Saluran pencernaan Sel epitel flux konstan : 20-50 juta sel di
duodenum : mati & regenerasi Kolon 10 kali lipat
CIN, cervical intraepithelial neoplasia; CIS. carcinoma in situ; DCIS, ductal carcinoma in situ: LCIS. lobular carcinoma m situ: PIN, prostatic inlraepithelial neoplasia
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Evidence for adenoma-to-carcinoma progression
microsatellite instability (MSI)
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Pertumbuhan kanker akumulasi perubahan genetik dan epigenetik
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Dimulai dari mutasi pada kromosom 5 Perkembangan mutasi melibatkan resistensi sel
Alternative paths during cancer progression
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Metaplasia awal aneuploid, tetraploid, LOH
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tumor sporadic menyebar pada kelompok2 sel yang mungkin berbeda tempat Field cancerization
Perkembangan kanker mengikuti teori evolusi Darwin Seleksi Clonal expansion
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Dalam jaringan kanker tidak semua sel memiliki kemampuan tumorigenik
Figure 11.14a The Biology of Cancer (© Garland Science 2007)
Pada tumor otak CD133 brain tumor stem cell antigen
Figure 11.15 The Biology of Cancer (© Garland Science 2007)
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Mutasi pada sekelompok populasi sel dapat diteruskan Asymmetric cell division ke sekelompok populasi sel, tetapi tidak ke kelompok lain karena adanya keterbatasan potensi proliferasi sel Symmetric cell division
Pada tumor terdapat diversifikasi klon sel karena adanya tingkat mutasi yang tinggi berbeda pada pasien berbeda
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An adenoid basal carcinoma (ABC) of the cervix from a 94year-old woman small basaloid islands infiltrate the cervical stroma (red circles). Columnar cell differentiation within such a nest of basaloid cells (green circle). neoplastic squamoid cells (yellow, blue)
EGF (green) and VEGF (red) receptors reveals great phenotypic diversity within small sectors of these tumor xenografts; cells
CSC from glioblastoma tumors differentiate in vitro into at least two distinct lineages of neuroectodermal cells, one exhibiting neuron-specific β-tubulin (red) and the other the astrocyte GFAP (glial fibrillary acidic protein) marker (green).
Tumorigenesis diawali minimal akibat 2 gen onkogen mutan yang berkolaborasi
Figure 11.23 The Biology of Cancer (© Garland Science 2007)
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One or two oncogenic lesions do not suffice to generate full-blown tumors
Table 11.2 The Biology of Cancer (© Garland Science 2007)
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Inisiasi Double mutation tumorigenesis
five distinct cellular regulatory circuits needed to be altered experimentally before human cells can grow as tumor cells in immunocompromised mice : (1) the mitogenic signaling pathway controlled by Ras (2) the cell cycle checkpoint controlled by pRb (3) the alarm pathway controlled by p53 (4) the telomere maintenance pathway controlled by hTERT (5) the signaling pathways controlled by protein phosphatase 2A
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passage through each cell cycle creates the danger of genome alterations, this suggests that the risks of cancer can vary enormously from one species to the next The bumblebee bat of Thailand
The blue whale has a body weight of about 1.3 × 108 g, reaches sexual maturity in 5–10 years, and has a life span of about 80 years ~ human Etruscan shrews reach reproductive age by 3–4 weeks
• The bat and the whale together with the approximately 40-fold difference in life span suggests a difference of more than 109 in the number of cell divisions that the two organisms experience in a lifetime • Metabolic rate of the small mammals may be as much as 103 times higher than the whale’s, and since much of the mutational burden of the cell genome derives from by-products of oxidative metabolism the blue whale may experience only a 106fold higher risk of cancer than the bat
Initiator : DMBA (7,12dimethilbenzanthrace ne) karsinogen Promotor : nonkarsinogeneik – TPA (12-Otetradecanoylphorbol -13-acetate)
Figure 11.28 The Biology of Cancer (© Garland Science 2007)
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Senyawa toksik dan mitogenik dapat berperan sebagai promotor tumor Rokok mengandung berbagai karsinogen
mutagenik, misalnya 3-metilkolanthrene Ethanol : mutagenik lemah Estrogen, progesteron mitogenik
Dapat saling bekerja sama dalam menyebabka n kanker pada mulut, throat
▪ Makin banyak siklus menstruasi dialami resiko breast cancer meningkat
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Perkembangan adenoma & karsinoma kolon dengan adanya Infeksi Helicobacter pada kolon Infeksi virus carcinoma hepatocellular
Inflamasi kronik pada empedu menyebabkan kanker)
Aspirin & sulindac – antiinflamasi menurunkan insiden kanker Kanker pankreas menurun ½ kali dengan aspirin Kanker lambung menurun 40% dengan aspirin TPA PKC IKK NFkBTNF inflamasi Shutdown IKK signaling pathwal supression colorectal tumor formation
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Stimulus inflamasi menyebabkan tertariknya sel-sel inflamasi ke daerah inflamasi + sel endotel produksi TNF- aktivasi jalur NF-kB TNF-, antiapopotik, protein mitogenik & COX-2 meningkat
Peranan promotor: Stimulasi clonal
expansions Promotor mempertinggi jumlah mutan lewat replikasi Repeated cycles growth & division pemendekan telomer BFB
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Figure 11.43 The Biology of Cancer (© Garland Science 2007)
Figure 11.44 The Biology of Cancer (© Garland Science 2007)
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